Atrial Fibrillation, Anticoagulation and Vitamins for ...120: 897-902 / Oden et al. Thromb Res 2006; 117: 493-9 Adjustedodds ratio for ischaemic stroke and intracranial bleeding in

Atrial Fibrillation, Anticoagulationand Vitamins for Homocysteine

Prof. J. David Spence M.D.

1The screen versions of these slides have full details of copyright and acknowledgements

1

Atrial Fibrillation, Anticoagulation and Vitamins for Homocysteine


Stroke Prevention & Atherosclerosis Research Centre

Robarts Research Institute

London, Canada

[email protected]://www.imaging.robarts.ca/sparc

2

Stroke seriesPerspective and Pathogenesis

1. Cerebrovascular disease: introduction and perspective (41 mins) Prof. Vladimir Hachinski –

Western University, Canada

2. Basic anatomy, physiology and pathophysiology of the cerebral circulation for the physician

(32 mins) Prof. Jean-Claude Baron – Cambridge University Hospitals, UK

3. Pathophysiology of cerebral ischemia (43 mins) Prof. Wolf-Dieter Heiss – Max Planck Institute

for Neurological Research, Germany

Diagnosis

4. The clinical diagnosis of stroke and stroke subtypes (42 mins) Prof. Louis Caplan – Beth Israel

Deaconess Medical Center and Harvard University, USA

5. The investigation of stroke (30 mins) Dr. Bart Demaerschalk – Mayo Clinic Arizona, USA

Treatment

6. General management (27 mins) Prof. Bo Norrving – Lund University Hospital, Sweden

7. The treatment of stroke: specific management - thrombolysis plus (35 mins) Prof. Nils Wahlgren

– Karolinska University Hospital, Sweden

8. The deteriorating stroke (36 mins) Prof. Werner Hacke – University of Heidelberg, Germany

Rehabilitation

9. Stroke rehabilitation (42 mins) Prof. Robert Teasell – University of Western Ontario, Canada

10. Rehabilitation: the chronic phase (42 mins) Prof. Lalit Kalra – King’s College London School

of Medicine

3

Disclosures

• Interest in vascularis.com

• Lecture honoraria/travel support from Bayer, Merck,

Boehringer-Ingelheim, Pfizer

• Research support for investigator-initiated projects

from Pfizer

• Contract research with many pharma/device companies:

all of the above, plus Takeda, BMS, Servier, Wyeth, Miles,

Roussel, NMT, AGA, Gore

• Grants from CIHR, Heart & Stroke Foundation, NIH/NINDS




4

Stroke and aging population

1. Economist 2014 2. AHA Statistics 2007

Stroke

0

2

4

6

8

10

12

14

20-34 35-44 45-54 55-64 65-74 75+

Perc

en

t

Men

Women

CAD

0

2

4

6

8

10

12

14

16

18

20-34 35-44 45-54 55-64 65-74 75+

Perc

en

t

5

Atrial fibrillation and age

• At age 50: 1.5% of stroke

• At age 80-89: 23.5% of stroke

(probably a higher proportion now)

Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke:

the Framingham Study Stroke. 1991; 22: 983-8

6Bsaed on: Go AS et al. JAMA 2001; 285: 2370-2375

Projected number of adults with atrial fibrillation in the United States

between 1995 and 2050

• 1995:

• 2050 (expected):

2,080,000

5,610,000




7

Diagnosing cardioembolic stroke

• Negative evidence

‒ Normal arteries, normal blood pressure

‒ Not lacunar

‒ No indication of vasculitis

• Positive evidence

‒ Clinically embolic

‒ Multiple vascular territories

‒ Echo, Holter, TCD bubble study

8

Baseline carotid plaque area as a predictor of 5-year risk of stroke, MI, death(after adjustment for risk factors*)

*Age, sex, SBP, tChol, pack-yrs, tHcy, diabetes, Rx lipids and BP

Stroke 2002; 33: 2916-2922

9

“Normal arteries”

• Not just no stenosis: also little plaque

• Not just young people

• Plaque measurement very useful

79 y.o. woman

Composite drawing of all plaques in extracranial carotids

Cryptogenic stroke

72 y.o. man




10

Ischemic stroke subtypes are changing

• Better BP control

• More statins

Bogiatzi C ….Spence JD. Stroke. 2014 Sep 11

11

Ischemic stroke subtypes are changing

Bogiatzi C ….Spence JD. Stroke. 2014; 45: 3208-13

Before 2005 After 2009

• Cardioembolic strokes more common,

large artery strokes less common

12

Treat early on clinical grounds

Purroy F et al. Stroke 2007; 38; 3225-3229

Anticoagulate pending the result of echo, Holter etc.




13

AF, aging and under-anticoagulation

Medicare: only 2/3 of appropriate candidates receive warfarin1

Canadian Stroke Registry2: Patients who should have been

on warfarin

• Only 40% were receiving warfarin

• 30% were on antiplatelet therapy

• 29% were receiving neither

• Only 10% of patients admitted with stroke and known AF

were anticoagulated appropriately to an INR of 2 to 3

• Even with AF and previous stroke/TIA, only 18%

appropriately anticoagulated

• New anticoagulants (e.g. dabigatran, rivaroxaban) may help3

1. Birman-Deych E et al, Stroke 2006; 37: 1070-4

2. Gladstone, DJ. et al. Stroke 40, 235-240 (2009)

3. Spence JD. Nature Reviews Cardiology 2009; 6: 448 – 450

14

Antiplatelet agents are not anticoagulants

15

Activated platelets




16

Retinal embolus of platelet aggregates

Fisher CM. Neurology. 1959 May; 9(5): 333-47

17

White thrombus vs. red thrombus

• White thrombus: platelet aggregates

‒ Fast flow, arteries

‒ Treatment: antiplatelet agents

• Red thrombus: fibrin polymer with entrapped RBCs

‒ Stasis, veins, AF, recent MI, ventricular aneurysm

‒ Treatment: anticoagulants

Deykin D. New Engl J Med 1967; 276: 622-628

Caplan L. Rev Neurol Dis 2007; 4: 113-121

18

Adding clopidogrel to ASA only reduces stroke risk

by 0.67%, NNT 149

Connolly SJ et al. Ann Intern Med 2011 155: 579–586

Antiplatelet agents don’t work

in atrial fibrillation




19SPAF III Lancet 1996; 348(9028): 633-638

Adjusted dose warfarin vs. low-dose warfarin plus aspirin

It’s all about INR

20

ASA vs. warfarin in elderly: BAFTA study

• Fatal or disabling stroke, intracranial

haemorrhage, or clinically significant

arterial embolism

• No significant increase in bleeding

with warfarin

• 973 patients with AF age > 75

• Annual stroke risk 3.4% with ASA, 1.6% with warfarin

Mant J et al. Lancet 2007; 370: 493–503

p=0·003

21

ASA less effective than warfarin for stroke prevention in ASA trials

Adapted from Hart et al. Ann Intern Med 2007; 147: 590-592

Warfarin reduces stroke by ~ 50%, compared to aspirin




22

Poor INR control increases risk of stroke in the real world

Adapted from Gallagher et al. Thromb Haemost 2011; 106: 968-77

Stroke survival in 37,907 AF patients – UK General Practice Research Database

(27,458 warfarin users and 10,449 not treated with an antithrombotic)

100

90

80

0 20 40 60 80 100

95

85

75

I I I I I I

No warfarin

Months

% o

f p

ati

en

ts w

ith

ou

t str

oke

> 70

61-70

51-60

41-50

31-40

< 30

%TTR

23

Warfarin will continue to be used

• Cost

• Prosthetic valves

• Renal failure

Dabigatran Warfarin

So we still need to do better with it

Spence JD. J Neural Transmission: 2013; 120: 1447-1451

24

Narrow therapeutic range

Adapted from: Fuster et al. Circulation 2011; 123: e269-e367. / Hylek and Singer. Ann Intern Med 1994;

120: 897-902 / Oden et al. Thromb Res 2006; 117: 493-9

Adjusted odds ratio for ischaemic stroke and intracranial bleeding in relation to INR

20

15

10

5

1

Od

ds r

ati

o

1.0 INR2.0 3.0 4.0 5.0 6.0 7.0 8.0

Intracranial bleeding risk

Ischaemic stroke risk

Ischaemic stroke riskIntracranial bleeding risk




25

Genetics of warfarin response

• Polymorphism of warfarin response VKORC1

(vitamin K receptor)

• Polymorphism of warfarin metabolism CYP2C9

• Huge range of inter-individual differences

in both metabolism and response to warfarin

• Individualized therapy better using genotyping

Schwarz, U.I. et al. N. Engl. J. Med. 2008; 358: 999-1008

26

Receptor polymorphism

Schwarz,U.I. et al. N. Engl. J. Med. 2008; 358: 999-1008

• VKORC1 haplotype had a significant effect on the time

that was required to reach the first INR

within the therapeutic range (P = 0.02) and the time

to the first INR of more than 4 (P = 0.003)

‒ A/A: 32

‒ A/non-A: 129

‒ Non-A/non-A: 135

• There was much more bleeding

among patients with polymorphism

27

Metabolism polymorphism

Schwarz,U.I. et al. N. Engl. J. Med. 2008; 358: 999-1008

• CYP2C9 genotype did not significantly affect the time

to the first INR within the therapeutic range

• Carriers of CYP2C9*2 and CYP2C9*3 variant alleles

did reach a first INR of more than 4 earlier than did patients

with the wild-type allele (P = 0.03)

‒ *1/*1: 204

‒ *1/*2 or *1/*3: 79

‒ *2/*2, *3/*3 or *2/*3: 1

• The time to a high INR was earlier

in patients with polymorphisms




28

Aspirin vs. apixaban in AF: AVERROES trial

Connelly SJ et al. N Engl J Med. 2011 Mar 3; 364(9): 806-17

Stroke or systemic embolism:

hazard ratio with apixaban, 0.45 (95% CI, 0.32–0.62)

29

Aspirin vs. apixaban in AF

Connelly SJ et al. N Engl J Med. 2011 Mar 3; 364(9): 806-17

Major bleeding:

hazard ratio with apixaban, 1.13 (95% CI, 0.74–1.75)

30

Stroke or systemic embolism

MajorBleeding

Apixaban vs. ASA in TIA/stroke

No TIA/stroke TIA/stroke

HR 0.51 (95% CI 0.35-0.74)

HR 0.29 (95% CI 0.15-0.60)

HR 1.08 (95% CI 0.64-1.80) HR 1.28 (95% CI 0.58-2.82)

Cu

mu

lativ

e h

aza

rdC

um

ula

tive h

aza

rd

Time (months)

Diener H-C et al. Lancet Neurol 2012; 11: 225–31

Time (months)

AspirinApixaban




31Based on Hart Ann Int Med 1999; 131: 492

CCS guidelines

• Compared to placebo/control,

the risk reduction with warfarin is 64%

• Patients need anticoagulants if they have AF

32

It is a mistake to use antiplatelet agents for AF

• The elderly benefit from anticoagulation

more than younger patients1, 2

• It would take 295 falls to equal the risk

of not anticoagulating in AF3

• Risk of serious bleeding is not higher on anticoagulation

than on antiplatelet agents4

1.van Walraven C, et al. Stroke. 2009; 40: 1410-6

2.Spence JD. Nat Rev Cardiol. 2009; 6: 448-50

3.Man-Son-Hing M et al. Arch Intern Med 1999; 159: 677–685

4.Flaker GC, et al. Stroke. 2012; 43: 3291-7

33

Controlling the INR matters

Hylek EM et al. Stroke 2008; 39: 3009-3014

P=0.0004

Annual stroke risk

SPORTIF III 2.3%

SPORTIF V 1.16%




34

Warfarin is impossible to use well

• In clinical trials, time in target INR only 60%

• In the real world:

‒ Only 35% of patients with AF on warfarin

‒ Of those only 50% of the time in target INR1

• One trick to reduce INR turbulence is to use a small dose

of vitamin K daily2

1. Samsa GP et al. Arch Intern Med 2000; 160: 967–973

2. Rombouts EK et al. J Thromb Haemost 2007; 5: 2043–2048

35Spence JD J Neural Transm 2013; 120: 1447-1451

Drug interactions with warfarin

36

Real-world warfarin bleeding, much higher and early

• This is why doctors

are afraid to anticoagulate

Gomes T et al. CMAJ. 2013; 185: E121-7




37

Under-anticoagulation doesn’t work

• 69 yo woman

with mitral stenosis

• Stroke from AF

• INR 1.5 x 22 days

• Surgical removal

of thrombus

at day 54

Tsuda Y et al. Stroke 1990; 21; 1375-1376

38

Seek AF, and ye shall find it1

1. Tayal AH, Callans DJ. Neurology 2010; 74: 1662–1663

2. Gaillard N et al. Neurology 2010; 74: 1666–1670

3. Wallman D et al. Stroke 2007; 38: 2292–2294

4. Rizos T et al. Stroke. 2012; 43: 2689-2694

5. Flint AC et al. Stroke. 2012; 43: 2788-2790

In cryptogenic stroke with no AF at baseline

• 1-4 months of telephonic ECG turned up AF in 9.2%2

• 7-day loop recorder at 0, 3 and 6 months: AF in 26%3

• Continuous monitoring in stroke unit better than Holter4

• 30-day monitoring 11%5

• EMBRACE study 3% on Holter, 16% long-term (30 day)

• Implantable monitor 3 years: 23%

39

EMBRACE study intervention

• Event-triggered loop recorder (Braemar Inc., ER910AF)

– Automatically records AF

– Memory storage capacity: 30 minutes

– Programmed to record up to 11 events, max. 2.5 minutes per event

• Accuheart electrode belt (Cardiac Bio-Systems Inc.)

– Dry electrode technology (without adhesive skin-contact electrodes)

• Worn for 30 days or until AF detected

• Data handling

– Recorded data transmitted trans-telephonically

to central station

– ECG tracings of all events printed and interpreted centrally

by one physician blinded to clinical information

– Results report sent to patient’s study physician




40

EMBRACE trial

Gladstone D et al. N Engl J Med 2014; 370: 2467-77

• 527 patients with cryptogenic stroke

• Age 73 years; 54% male; automated recorder belt vs. repeat Holter

• At 3 months, 16.1% with AF vs. 3.2% p = 0.001

41

CRYSTAL AF study

• 441 patients with cryptogenic stroke

• 63% male, age 61.5 years; implantable device

• 6 months rate with an implantable device was ~ 10%

• After 36 months it was just above 30%

• Many patients with cryptogenic stroke in whom we suspect

a cardio-embolic stroke, have undetected intermittent AF

Based on: Sanna T et al. N Engl J Med. 2014; 370: 2478-86

42

CCS guidelines

www.ccs.ca

• If a patient had a stroke and his CHADS2 score is > 2,

he needs anticoagulation therapy

• If the CHADS2 score is 6 the adjusted rate of stroke/year is 18%

• These patients should not get anti-platelet agents

The CHADS2 score is useful in deciding which patient needs anticoagulation therapy




43

Recommendations – antithrombotic for AF

When OAC therapy is indicated, most patients

should receive (NOA) in preference to warfarin

(Conditional recommendation. High quality evidence)

CCS guidelines (2)

www.ccs.ca

44

Most thrombi in left atrial appendage

>90% of thrombi in non-valvular AF are in the atrial appendage

45

Other approaches

• Prophylactic removal of atrial appendage

during cardiac surgery

• Thoracoscopic removal of LA appendage

• Insertion of device in LA appendage

Onalan O, Crystal E. Stroke 2007; 38; 624-630




46

Protect - AF trial

• AF patients randomized to conventional warfarin vs. Watchman device

After 900 patient-years:

• 32% of primary outcome: absence of ischemic & hemorrhagic stroke,

CV /unexplained death, systemic embolism

BUT:

• >25% of patients did not take warfarin

• Implantation only successful in 90%

• 12.3% had serious complications

– 4 had to have device removed

– 2.2% required surgery

– Higher risk in low-volume centres

Maisel WH. N Engl J Med. 2009 Jun 18; 360(25): 2601-3

47

PLAATO device

• In feasibility studies n=108

• Successful implantation

in 97%;

• 65% reduction of stroke

• Trial under way

Onalan O, Crystal E. Stroke 2007; 38; 624-630

48

European PLAATO study

180 patients with AF and TIA/Stroke or CHADS > 2

and contraindications to warfarin

• Successful occlusion of atrial appendage in 90%

• 2 deaths

• 6 cardiac tamponade, 2 requiring surgery

• 1 device too small and embolized to aorta; snared successfully

• 2.3% strokes per year vs. expected 6.6% for CHADS 2

Bayard YL et al. EuroIntervention. 2010 Jun; 6(2): 220-6




49

New era in anticoagulation

Atarashi H. Circ J. 2011; 75: 1819-20

Intracranial bleeding?

ApixabanRivaroxaban

Dabigatran

50

Novel oral anticoagulants –pharmacological properties

1. Xarelto® PM, July 18, 2012; 2. Pradaxa ® PM November 12, 2012; 3. Eliquis® PM November 27, 2012; 4. Goette Trends Cardiovasc Med. 2013; 23: 128-34

P-gp = P glycoprotein

Characteristic Rivaroxaban1 Dabigatran2 Apixaban3

Target Factor Xa Factor IIa Factor Xa

Prodrug No Yes No

Dosing OD BID BID

Bioavailability, % 80-100%* 6.5% 50%

Half-life 5-13h 12-14 h 8-15 h

Renal clearance (unchanged bioavailable drug)

~33% 85% ~25%4†

Cmax 2-4 h 1-2 h 3-4 h

Drug interactions

Strong inhibitors

of both CYP3A4 and P-gp

P-gp inhibitors

Strong inhibitors

of both CYP3A4 and P-gp

51

Dabigatran vs. warfarin in atrial fibrillation

n =18,113Median follow up 2yrs

Connolly SJ et al. N Engl J Med 2009; 361

pDabigatran150 mg

Dabigatran110 mg

Warfarin(INR 2-3)

Risk/year

0.0013.11%2.71%3.36%Major bleeding

0.0010.10%0.12%0.33%Hemorrhagic stroke

0.046.91%7.09%7.64%Major vasc. event, major bleed, death




52

Dabigatran plasma concentration and outcomes

Reilly PA et al. J Am Coll Cardiol. 2014; 63: 321-8

53

Therapeutic range for dabigatran

Reilly PA et al. J Am Coll Cardiol. 2014; 63: 321-8

54

New oral anticoagulants: total drug exposure (AUC) with declining renal function

AU

C r

atio v

s. N

orm

al re

nal fu

nction

1. Xarelto® PM, July 18, 2012; 2. Pradaxa ® PM November 12, 2012; 3. Goette Trends Cardiovasc Med.2013 [Epub ahead of print]; 4. Eliquis® PM November 27, 2012

Rivaroxaban (33% cleared renally*)1

Dabigatran(85% cleared renally)2

Apixaban(40-50% cleared renally†)3




55

Need for blood levels of dabigatran

• Only 3-7% bioavailable

• Subject to large effects of:

– Drug interaction

– Renal function

Moore TJ et al. BMJ 2014; 349: g4517

56

Rivaroxaban vs. warfarin in AF

N= 14,264

INR therapeutic 55%

of the time

1 outcome HR 0.79 p=0.001

Riva Warf

Fatal bleeding 0.2% 0.5% p=0.003

Intracranial Bleeding 0.5% 0.7% p=0.03

Rocket trial. Patel MR et al. N Engl J Med. 2011; 365: 883-91

• Stroke or systemic embolism occurred in:

– 188 patients in the rivaroxaban group (1.7% per year)

– 241 patients in the warfarin group (2.2% per year)

(hazard ratio in the rivaroxaban group, 0.79;

95% confidence interval [CI], 0.66 to 0.96; P<0.001 for noninferiority)

57

Apixaban vs. warfarin in AF

n= 18,201

CHADS2 score

Apixa Warf

Mean 2.1±1.1 2.1±1.1

INR therapeutic 62.2% of timeAristotle trial. Granger CB et al. N Engl J Med 2011; 365: 981-92

• The primary outcome of stroke or systemic embolism:

– 212 patients in the apixaban group (1.27% per year)


(hazard ratio in the apixaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.95;

P<0.001 for noninferiority and P = 0.01 for superiority)

• Major bleeding (defined according to ISTH criteria):

– 327 patients in the apixaban group (2.13% per year)


(hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P<0.001)




58

ICH in ROCKET

Hankey GJ et al. Stroke 2014; 45: 1304-1312

59

New oral anticoagulants vs. warfarin in atrial fibrillation; apixaban, dabigatran, rivaroxaban

Klein L. Ann Intern Med. 2012 Sep 18; 157(6): JC3-2

Outcomes Weighted event rates At a median 657 to 730 d

NOA War RRR (95% CI)

Stroke and systemic embolism 2.7% 3.5% 22% (8 to 33)

Ischemic or unspecified stroke 1.9% 2.2% 13% (1 to 23)

Hemorrhagic stroke 0.4% 0.8% 55% (32 to 69)

All-cause mortality 5.6% 6.3% 12% (5 to 18)

Vascular mortality 3.4% 3.9% 13% (2 to 23)

Myocardial infarction 1.3% 1.4% 4% (−26 to 27)

Major bleeding 5.0% 5.7% 12% (−9 to 29)

Intracranial bleeding 0.7% 1.3% 51% (34 to 64)

Gastrointestinal bleeding 2.2% 1.8% RRI 25% (−9 to 72)

60

Reversal of Xa inhibitor with prothrombin complex concentrate (PCC)

Eerenberg ES et al. Circulation. 2011; 124: 1573-9

Rivaroxaban 20mg BID

for two and a half days

PCC or placebo infusion

Rivaroxaban 20mg BID

for two and a half days

PCC or placebo infusion

Se

co

nd

s

Pe

rce

nta

ge

s (%

)

Time Time

PT ETP

Placebo

PCC

Placebo

PCC




61

Reversal with perosphere

Ansell JE et al. N Engl J Med. 2014 371(22): 2141-2

In a clinical trial in healthy volunteers, there was a marked reduction in clotting time

with a dose response

62

Homocysteine: alive again

• MI ≠ STROKE

• MI – almost all due to plaque rupture; thrombosis

is secondary to occlusion

• STROKE: atheroembolic, dissection, vasculitis,

small vessel disease (lacunar infarctions),

cerebral vein thrombosis

– Coagulation more important

– Cardiac emboli

AF, MI, ventricular aneurysm

Paradoxical embolism

Spence JD. Lancet Neurology 2007; 7: 830-838

63

Homocysteine: steep dose-response curve(schematic)

Based on: Nygård O et al. N.Engl.J.Med. 1997; 337: 230-6

Homocysteine blood levels

Ris

k o

f ca

rdio

va

scu

lar e

ve

nt




64

Biological plausibility is overwhelming

• Increased thrombosis

• Impaired endothelial function

• LDL, HDL synthesis

• Oxidative stress including oxidized LDL

• Causal in animal models1

1. Zhou J et al. Atherosclerosis. 2003; 168: 255-62

65

Homocysteine and venous thrombosis

• Excess of high tHcy and prothrombin gene mutation

in cerebral venous thrombosis1

• High tHcy a risk factor for venous thrombosis2

• High tHcy a risk factor for retinal vein occlusion3

1. Ventura P. Cerebrovasc Dis. 2004; 17(2-3): 153-9

2. den Heijer M. Clin Chem Lab Med. 2003; 41: 1404-7

3. Chua B et al. Am J Ophthalmol. 2005 Jan; 139(1): 181-2

66

Homocysteine and atrial fibrillation

• In patients with AF

• Stroke risk is 4-5 fold higher with tHcy > 14




67Poli D et al. Stroke 2005; 10: 2159-63

Homocysteine increases risk in atrial fibrillation

Homocysteine>90th percentile

Homocysteine<90th percentile

p=0.006

Time (days)

68

Vitamin B12 deficiency

• There are about 8 ways for B12 absorption to go wrong:

‒ Gastric acid: gastrectomy, atrophic gastritis, omeprazole

‒ Intrinsic factor

‒ Pancreatic 3rd factor

‒ Terminal ileum: Crohn’s etc.

‒ 2 transport proteins: transcobalamin II

Genetic deficiency, antibodies

• In Framingham, 40% of elderly have levels <258 pmol/L1,

which represents insufficient B12 to maintain normal MMA

• 20% of elderly have B12 deficiency2

1. Lindenbaum J et al. Am J Clin Nutr 1994; 60: 2-11

2. Andres E. et al. CMAJ 2004 Aug 3; 171(3): 251-9

69

Baseline tHcy by serum B12 (pmol/L), adjusted for age, sex, smoking and GFR (NHANES)

Bang H, Mazumdar M, Spence D. Neuroepidemiology. 2006; 27(4): 188-200

Segmented regression




70

Threshold B12 level for MMA and tHcy

Vogiatzoglou A … Refsum H. Clinical Chemistry 2009; 55: 12 2198–2206

Hordaland study n=6946

711. Spence JD. Stroke 2006; 37: 2430-5

2. Vogiatzoglu A et al. Clin Chem 2009; 55: 2198-206

400pmol/L is safe to exclude metabolic B12 deficiency2

Metabolic B12 deficiency in the stroke prevention clinic

• Only ~ 20%

of serum total

B12 is active:

– Need to do

tests of B12

function

72

• Proportion

of patients

with various B12

levels in the Stroke

Prevention Clinic

• Only 26%

had serum B12

in the clearly

adequate range

above 400 pmol/L




73

Metabolic B12 deficiency in vascular patients

• Define by methylmalonic acid

(or tHcy in folate-replete state)

• 11% age <50

• 12% age 51-71

• 30% age >71

Spence JD. Stroke 2006; 37: 2430-5

74

tHcy>14 μmol/L by age

Spence JD. Lancet 2009; 373: 1006

n= 2372 - patients referred to stroke prevention clinic

75

VISP efficacy analysis

P=0.02

Spence JD et al. Stroke. 2005; 36: 2404-2409

Cu

mu

lativ

e p

erc

en

tag

e

Follow up time in days

Coronary/stroke/death

Groups:

1=treat L, B12<median; 2=treat H, B12<median;

3= L, B12≥median; 4=treat H, B12>median




76

HOPE-2 trial

Based on: Refsum H, Smith AD. N Engl J Med. 2006; 355: 207

23% reduction of stroke in the HOPE-2 trial (p=0.03) –first study to use 1 mg of vitamin B12

77

Reduction of stroke in SuFolOM3 trial

Galan P, et al. BMJ. 2010; 341: c6273

p=0.04

78

VITATOPS

Hankey GJ et al. Lancet Neurol 2012; 11: 512–20

• n= 1463 not on antiplatelet therapy

• HR 0·76 (0·60–0·96)

for stroke/MI/vascular death




79Yi Q, Hankey G, Spence JD. Unpublished data

Cyanocobalamin dose was lower in VITATOPS – 500 mcg

VITATOPS stratified by GFR

80

JAMA. 2010; 303(16): 1603-1609

81

Stroke, MI, death1

1. JAMA. 2010; 303(16): 1603-1609

2. JAMA. 2010; 304(6): 636-637

The greatest harm of vitamin therapy was in patients with GFR<502




82

Possible harmful effects of folic acid

Based on: Loscalzo, J N Engl J Med 2006; 345: 1629-32

Folic acid does not reverse the increase in asymmetric dimethylarginine that accompanies

high homocysteine levels

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Cyanide from B12

Koyama K et al. Nephrol Dial Transplant. 1997; 12: 1622-8

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Interesting lessons

• Clinical trials are blunt instruments for studying

vascular biology

• Subgroup analyses can be very informative

• We should probably be using methylcobalamin

or hydroxycobalamin instead of cyanocobalamin

• ? Tetrahydrofolate instead of folic acid (particularly

where folic acid fortification of the grain supply is in effect)

Spence JD, Stampfer M. JAMA 2011; 306: 1260-1261




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What’s the secret?

To select the appropriate treatment, find the cause of the TIA/stroke

86

• U/S: symptomatic severe (moderate)

carotid stenosis – endarterectomy

• MRA/CTA: basilar occlusion ?anticoagulate

– Intracranial stenosis ?ASA/clopidogrel

• ECG/Echo/Holter/TCD: cardiac source: anticoagulate

• Vasculitis (e.g. giant cell arteritis – prednisone)

• TCD – intracranial stenosis ?Anticoagulate

• TCD with bubble test for paradoxical embolus-

anticoagulate or ?close PFO

• Aortic atheroma - intensive medical Rx,

?anticoagulate, ??surgery

Find the cause, and treat it

87http://www.imaging.robarts.ca/SPARC/ [email protected]




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Documents

Atrial Fibrillation, Anticoagulation and Vitamins for ...120: 897-902 / Oden et al. Thromb Res 2006; 117: 493-9 Adjustedodds ratio for ischaemic stroke and intracranial bleeding in